Advanced Glycation End-Product Carboxymethyl-Lysine and Incident Heart Failure and Atrial Fibrillation in Older Adults.

Background: Advanced glycation end-products result from chemical modification of proteins under conditions of hyperglycemia or oxidative stress common with advancing age. Advanced glycation end-product (AGE) formation alters vascular and cardiac structure and function, yet the prospective associations of circulating AGEs with heart failure (HF) and atrial fibrillation (AF) have not been studied.

Methods: We evaluated the associations of serum N-carboxymethyl-lysine (CML), a major AGE in tissue proteins, and incident HF and AF in the CHS (Cardiovascular Health Study), a population-based cohort of older adults.

A semi-empirical Bayes approach for calibrating weak instrumental bias in sex-specific Mendelian randomization studies.

Strong sex differences exist in sleep phenotypes and also cardiovascular diseases (CVDs). However, sex-specific causal effects of sleep phenotypes on CVD-related outcomes have not been thoroughly examined. Mendelian randomization (MR) analysis is a useful approach for estimating the causal effect of a risk factor on an outcome of interest when interventional studies are not available.

Loss-of-function mutations ensure that response to immune checkpoint therapy is NOD2 be denied.

Loss-of-function mutations in NOD2 may predict positive response to PD-1 blockade monotherapy in cancer.

Aldosterone synthase inhibition: a novel bullet to fight cardiovascular-kidney metabolic syndrome.

Aldosterone is synthesized by the CYP11B2 enzyme, primarily in the zona glomerulosa of the adrenal gland. It exerts its classical effects on sodium and water balance in the renal distal nephron through binding to the mineralocorticoid receptor (MR). Excess aldosterone production or overactivation of the MR outside the distal nephron leads to cardiac, renal, and vascular injury by increasing oxidative stress and activating the inflammatory and fibrotic pathways.

Genetically determined body mass index is associated with diffuse large B-cell lymphoma in polygenic and Mendelian randomization analyses.

Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.

Risk of Opioid Overdose Associated with Concurrent Use of Hydrocodone and CYP3A4-inhibiting Calcium Channel Blockers: A Population-based Cohort Study.

Non-dihydropyridine calcium channel blockers (CCBs), including diltiazem and verapamil, inhibit cytochrome P450 3A4 (CYP3A4), an enzyme involved in the metabolism of hydrocodone, the most commonly used opioid in the United States (US). This study evaluated whether concomitant use of hydrocodone with CYP3A4-inhibiting CCBs increases the risk of opioid overdose compared to use of hydrocodone with amlodipine, a CCB that does not inhibit CYP3A4. Using three US databases (2000-2021), two cohorts were identified: (1) hydrocodone initiation while on CCB; and (2) CCB initiation while on hydrocodone.

Size and Growth After NICU Discharge in Extremely Low-Birth-Weight or Extremely Preterm Infants.

Objective: Among extremely low-birth-weight (ELBW; <1000 g) or extremely preterm (EPT; <28 + 0 weeks) infants, we aimed to describe size indicators at 18 to 24 months of corrected age and growth from neonatal intensive care unit (NICU) discharge to follow-up and to examine infant and maternal determinants of those outcomes.

Methods: We studied 7301 ELBW/EPT children from 77 Vermont Oxford Network member hospitals. Continuous size indicators at 18 to 24 months were z scores of weight, length, head circumference, and body mass index based on World Health Organization standards.

Disease burden and health-related outcomes of patients discharged from hospital following a COPD exacerbation in the United States.

Background: Evidence on trajectory of readmission rates post-hospitalization for COPD exacerbations and combined cardiopulmonary risk in the U.S. is sparse.

Perspective: Food is Medicine: Hype or Hope?

Food is Medicine (FIM) initiatives are food-based nutrition interventions to prevent or manage chronic disease and improve overall health. It is increasingly embraced across healthcare systems, policy makers, and researchers as a promising strategy to address diet-related chronic diseases. Despite this enthusiasm, questions have been raised about whether FIM is overhyped given the still limited evidence.

A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease.

Background: Parkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in SNCA gene, encoding α-synuclein (aSyn), are linked to rare familial forms of PD.

Objective: Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD.

Reproducible single-cell annotation of programs underlying T cell subsets, activation states and functions.

T cells recognize antigens and induce specialized gene expression programs (GEPs), enabling functions like proliferation, cytotoxicity and cytokine production. Traditionally, different T cell classes are thought to exhibit mutually exclusive responses, including T1, T2 and T17 programs. However, single-cell RNA sequencing has revealed a continuum of T cell states without clearly distinct subsets, necessitating new analytical frameworks.

Multiple overlapping binding sites determine transcription factor occupancy.

Transcription factors (TFs) regulate gene expression by interacting with DNA in a sequence-specific manner. High-throughput in vitro technologies, such as protein-binding microarrays and HT-SELEX (high-throughput systematic evolution of ligands by exponential enrichment), have revealed the DNA-binding specificities of hundreds of TFs. However, they have limited ability to reliably identify lower-affinity DNA binding sites, which are increasingly recognized as important for precise spatiotemporal control of gene expression.

Pathogenic Cardiomyopathy-Associated Gene Variants and Prognosis in Atrial Fibrillation: Results in 18,000 Clinical Trial Participants.

Background: Genetic variants in cardiomyopathy genes are associated with risk of atrial fibrillation (AF), although data on clinical outcomes for AF patients with such variants remain sparse.

Objectives: We aimed to study the prognostic implication of rare cardiomyopathy-associated pathogenic variants (CMP-PLP) in AF patients from large, well-phenotyped clinical trials.

Methods: CMP-PLP carriers were identified using exome sequencing in 5 multinational trials from the Thrombolysis in Myocardial Infarction study group (ENGAGE AF, FOURIER, SAVOR, PEGASUS, and DECLARE), with replication in the EAST-AFNET-4 trial.

Equity in rhetoric and (in)action: a thematic analysis of Canada's approach to intellectual property rights in pandemics.

The Canadian federal government has consistently emphasized its commitment to global health equity. However, during the COVID-19 pandemic and its aftermath, Canada repeatedly resisted measures designed to promote equitable and timely global access to medicines through intellectual property (IP) sharing. This research study employs a qualitative, document-based thematic analysis to examine how Canada's rhetorical commitments to equity intersected with its policy actions across three key cases: Canada's Patent Act flexibilities surrounding the COVID-19 World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Waiver; Bolivia and Biolyse's efforts to navigate Canada's Access to Medicines Regime and the World Health Assembly's intergovernmental negotiating body's efforts to draft a treaty for pandemic prevention, preparedness and response.

Traffic-emitted ultrafine particles disrupt macrophage efferocytosis and resolution of allergic lung inflammation.

Background: Particulate matter (PM) in air pollution is a major health concern. PM includes ultrafine particles (UFPs - PM, particles of ≤ 0.1μm), which can evoke lung inflammation.

Pharmacologic interrogation of USP28 cellular function in p53 signaling.

Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed CAS-010, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor.

Measuring Psychological Well-Being and Behaviors Using Smartphone-Based Digital Phenotyping: An Intensive Longitudinal Observational mHealth Pilot Study Embedded in a Prospective Cohort of Women.

Background: Intensive measures of well-being and behaviors in large epidemiologic cohorts have the potential to enhance health research in these areas. Yet, little is known regarding the feasibility of using mobile technology to collect intensive data in the "natural" environment in the context of ongoing large cohort studies.

Objective: We examined the feasibility of using smartphone digital phenotyping to collect highly resolved psychological and behavioral data from participants in a pilot study with participants in Nurses' Health Study II, a nationwide prospective cohort of women.

Quantification of Differences in Sleep Measurement by a Wrist-Worn Consumer Wearable Compared to Research-Grade Accelerometry and Sleep Diaries of Female Adults in Free-Living Conditions.

Purpose: The objective of this study is to compare sleep measurements by a consumer-wearable with research-standard actigraphy coupled with sleep diaries in free-living female adults.

Methods: Forty-seven females in the Nurses' Health Study 3 (NHS3) participated in the Sleep and Physical Activity Validation Substudy (SPAVS), where they were asked to concurrently wear a consumer wearable (Fitbit Charge, Models 3 or 5) and a research-grade accelerometer (Actigraph, GT3X+ or Actisleep) on the same wrist and fill out a smartphone-based sleep diary for fourteen consecutive days. We compared measures of total sleep time (TST), time in bed (TIB), and sleep efficiency (SE) from the consumer wearable with actigraphy measures as our research-standard reference for TST and SE and self-reported sleep diary as our reference for TIB.

A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis.

Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies.

Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.

Optineurin (OPTN) is an autophagy adaptor protein involved in selective autophagy, including aggrephagy and mitophagy. Pathogenic mutations in OPTN have also been linked to amyotrophic lateral sclerosis, frontotemporal dementia, and glaucoma, supporting its role in the etiology of neurodegenerative diseases. Despite its established biological roles, knowledge about its potential contribution to Alzheimer's disease (AD) pathology and neuronal functioning is lacking.

What Do We Know About Prevention of Frailty in Women?

Frailty is a multidimensional syndrome associated with a state of vulnerability to external stressors. Though women have a longer life expectancy than men, they have a higher risk of frailty. Frailty is prevalent in women, affecting ∼9-15% of community-dwelling older women, and over 50% of nursing home residents.

Metabolomic signatures of hypocaloric dietary interventions associate with breast cancer risk in the Nurses' Health Study II.

Background: An individual's metabolic state plays a critical role in breast cancer (BC) risk, influenced by factors such as obesity and insulin signaling. Hypocaloric diets induce metabolic changes that influence these metabolic factors, thereby potentially influencing BC risk. However, it remains unclear whether metabolic profiles like those induced by such beneficial diets are associated with BC risk.

Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance.

We previously showed that infiltrating cytotoxic immune cells are reprogrammed to regulatory-like/exhausted cells within accepted kidney allografts through a 'defensive tolerance' mechanism. We observed a regulatory B cell (Breg) signature within the accepted kidney. Here we show that despite a Breg phenotype, neither B cell depletion nor the use of μMT recipients which lack B cells, resulted in kidney allograft rejection.

Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer.

Purpose: Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC.